Glicerinas Industriales, S.A. de C.V.

The U.S. Food and Drug Administration (FDA) inspected your drug manufacturing facility, Glicerinas Industriales, S.A. de C.V., FEI 3016420687, at Calle Uranio No. 80, Col. Arenales Tapatios, Zapopan, from May 8 to 12, 2023.

This warning letter summarizes significant deviations from Current Good Manufacturing Practice (CGMP) for active pharmaceutical ingredients (API).

Because your methods, facilities, or controls for manufacturing, processing, packing, or holding do not conform to CGMP, your API are adulterated within the meaning of section 501(a)(2)(B) of the Federal Food, Drug, and Cosmetic Act (FD&C Act), 21 U.S.C. 351(a)(2)(B).

We reviewed your June 5, 2023 response to our Form FDA 483 in detail.

During our inspection, our investigators observed specific deviations including, but not limited to, the following.

You repackage and supply drugs (API and excipients) to drug manufacturers that use them as components in finished pharmaceutical production. Some drugs, such as glycerin USP, are at higher risk of diethylene glycol (DEG) or ethylene glycol (EG) contamination. You failed to conduct adequate identity testing to monitor for the risk of DEG or EG contamination.

The use of ingredients contaminated with DEG or EG has resulted in various lethal poisoning incidents in humans worldwide. See FDA’s guidance document Testing of Glycerin, Propylene Glycol, Maltitol Solution, Hydrogenated Starch Hydrolysate, Sorbitol Solution, and Other High-Risk Drug Components for Diethylene Glycol and Ethylene Glycol to help you meet the CGMP requirements when manufacturing drugs, including repackaged drugs at high-risk for DEG or EG contamination at https://www.fda.gov/media/167974/download.

We previously informed you of CGMP requirements for identity testing for high-risk drug components, such as glycerin.

In response to this letter, provide:

A commitment to provide DEG and EG test results, no later than 30 calendar days from the date of this letter, from testing retains for all lots of drugs at high-risk for DEG or EG contamination.

A description of how you will test each lot for conformity with all appropriate specifications for identity, strength, quality, and purity.

A commitment to always conduct at least one specific identity test for each container of each lot of each shipment. In the case of glycerin, propylene glycol, and certain additional high-risk drugs we note that this includes the performance of parts A, B, and C of the United States Pharmacopeia (USP) monograph.

A comprehensive, independent review of your material system to determine whether all suppliers of raw material, containers, and closures, are each qualified and the materials are assigned appropriate expiration or retest dates. The review should also determine whether incoming material controls are adequate to prevent use of unsuitable drugs, containers, and closures.

A summary of your program for qualifying and overseeing contract facilities that test the drug you manufacture.

Your firm failed to investigate deviations from your quality specifications for your repackaged drugs. For example, your firm failed to adequately investigate observed contamination of particulates in numerous packaged drugs. According to your production records, the contamination included various unidentified colored particulates, reports of insects, hair, and fibers in your repackaged containers of glycerin, propylene glycol, and (b)(4).

Although your firm observed particulates in your repackaged drug components over a three-month period, you did not reject the lots and failed to fully identify a clear root cause for the contamination source. Your firm also failed to implement a corrective action and preventive action (CAPA) according to your procedure until after FDA cited your firm. You ultimately released the contaminated repackaged drugs to your customers without adequately investigating the extent of the contamination or identifying the various unidentified colored particulates found. Since you only began documenting the contamination after a revision to your production record in February 2023, it is unknown how long your repackaged drugs may have been contaminated with particulates.

In your response, you acknowledged that you did not investigate over 100 lots contaminated with particulates. Although you provided an investigation and CAPA, your investigation failed to assess the safety risk of contaminated drugs released to your customers, including customer notification. Furthermore, your response did not describe how your firm will remediate your investigation processes to ensure all out-of-specification (OOS) test results and deviations are fully investigated and appropriate CAPA implemented.

Inadequate investigations can lead to unidentified root causes, ineffective CAPA, and recurring problems that compromise the ability to manufacture safe and effective drug products.

In response to this letter, provide a comprehensive, independent assessment of your overall system for investigating deviations, discrepancies, complaints, OOS results, and failures. Provide a detailed action plan to remediate this system. Your action plan should include, but not be limited to, significant improvements in investigation competencies, scope determination, root cause evaluation, CAPA effectiveness, quality unit oversight, and written procedures. Address how your firm will ensure all phases of investigations are appropriately conducted.

Based upon the nature of the deviations we identified at your firm, you should engage a consultant qualified to evaluate your operations and to assist your firm in meeting CGMP requirements. The qualified consultant should also perform a comprehensive six-system audit1 of your entire operation for CGMP compliance and evaluate the completion and efficacy of your CAPA before you pursue resolution of your firm’s compliance status with FDA.

Your use of a consultant does not relieve your firm’s obligation to comply with CGMP. Your firm’s executive management remains responsible for resolving all deficiencies and systemic flaws to ensure ongoing CGMP compliance.

The deviations cited in this letter are not intended to be an all-inclusive list of deviations that exist at your facility. You are responsible for investigating and determining the causes of any deviations and for preventing their recurrence or the occurrence of other deviations.

FDA placed your firm on Import Alert 66-40 on January 16, 2024.

FDA had previously placed your firm on IA 66-79. FDA issued your firm warning letter #320-22-15 dated June 13, 2022, for refusing an inspection.

Correct any deviations promptly. FDA may withhold approval of new applications or supplements listing your firm as a drug manufacturer until any deviations are completely addressed and we confirm your compliance with CGMP. We may re-inspect to verify that you have completed corrective actions to any deviations.

Failure to address any deviations may also result in the FDA continuing to refuse admission of articles manufactured at Glicerinas Industriales, S.A. de C.V., Calle Uranio No. 80, Col. Arenales Tapatios, Zapopan, into the United States under section 801(a)(3) of the FD&C Act, 21 U.S.C. 381(a)(3). Articles under this authority that appear to be adulterated may be detained or refused admission, in that the methods and controls used in their manufacture do not appear to conform to CGMP within the meaning of section 501(a)(2)(B) of the FD&C Act, 21 U.S.C. 351(a)(2)(B).

This letter notifies you of our findings and provides you an opportunity to address the above deficiencies. After you receive this letter, respond to this office in writing within 15 working days. Specify what you have done to address any deviations and to prevent their recurrence. In response to this letter, you may provide additional information for our consideration as we continue to assess your activities and practices. If you cannot complete corrective actions within 15 working days, state your reasons for delay and your schedule for completion.

Send your electronic reply to CDER-OC-OMQ-Communications@fda.hhs.gov. Identify your response with FEI 3016420687 and ATTN: Bill Fowler.